Osteoarthritis (OA) affects nearly 27 million Americans and poses significant costs on both the patient's health and finances. For instance, researchers found that in a study of 84,647 adult women and 70,590 adult men with health insurance, due to a higher rate of OA, women had higher annual insurer health care costs than men ($4,833 vs. $4,036) and higher out-of-pocket expenditures ($1,379 vs. $694) and thus accounted for $118 billion of the total $186 billion increase in health care expenditures. Kotlarz et al., Arthritis Rheum. 2009; 60(12):3546-3553.
Causes of OA vary, but include aging joints, genetic predisposition, previous injuries and obesity. Symptoms of OA include joint pain, swelling, stiffness, loss of motion, diminution of activities of daily living, disability and loss of work. For example, patients with knee OA report knee pain and difficulty with walking, stair-climbing and housekeeping. Guccione et al., American Journal of Public Health, 1994; 84:351-358. Osteoarthritis may affect any joint, including the hand, wrist, neck, back, knee and hip. The knee is the most common lower limb site for OA, with the disease affecting the tibiofemoral and patellofemoral joints either in isolation or combination, with the medial tibiofemoral compartment as the most commonly affected. Ledingham et al., Annals of Rheumatic Disease 1993; 52:520-526.
The microscopic changes of OA typically begin with a disruption of the surface layer of cartilage, called the superficial zone. Functionally, of the four layers of cartilage present in joints, this is the most important. In non-diseased joints the cartilage surface is smooth, enabling joint surfaces to interact without friction, due in part to the molecule lubricin. However, the cartilage of the superficial zone begins to deteriorate as OA progresses triggering an irreversible process that eventually leads to the loss of underlying layers of cartilage. The integrity of the cartilage breaks down resulting in fragments of cartilage being dispersed in the joint causing reaction of the joint lining, inflammation and the symptoms of pain and swelling. Over time, exposed bone surfaces begin to grind painfully against one another. In addition there are architectural changes in the geometry of the adjacent bone resulting in deformity, instability, angulation and loss of motion.
Conventional thought is that articular cartilage in synovial joints has little or no potential for repair or restoration following injury or disease. Buckwalter J A, Mankin N J. Instructional Course Lectures, The American Academy of Orthopaedic Surgeons (AAOS)-Articular Cartilage. Part II: Degeneration and Osteoarthrosis, Repair, Regeneration, and Transplantation. J. Bone Joint Surg. Am., April 1997; 79: 612-32. The primary reason is that, unlike other tissues, it has no innate blood supply. Instead, it is a relative acellular tissue formed primarily of a matrix of water held in place with a network of mucopolysacccharides, which themselves are glucosamines made up in part of glucose molecules.
Management strategies for OA can be regarded as primary (reducing risk factors to lessen disease incidence); secondary (intervening to slow or prevent progression to serious disease); or tertiary (treating pain and disability). Dieppe et al., Rheum. Dis. Clin. N. Am. 2003; 29(4):687716. To date, most knee OA research has focused on tertiary strategies relating to pain management. Among these strategies, the primary emphasis has been on drug therapies, which typically include unwanted side effects and can be costly. Dieppe et al., BMJ 2004; 329(7471):867-868.
Non-operative treatment depends on the joint but often includes medication and exercise. For instance, OA patients are often treated with nonsteriodal anti-inflammatory drugs (NSAIDs) such as MOTRIN and CELEBREX. Alternatively, patients may be treated with the steroid hormone Cortisone, often by injection, which reduces inflammation by suppressing the immune system.
Viscosupplementation with hyaluronic acid (HA) is gaining popularity in the nonoperative management of OA. HA is believed by some to have anti-inflammatory, anabolic and chondroprotective actions thereby reducing pain and improving patient function. Strauss et al., American Journal of Sports Medicine, 2009 August; 37(8):1636-1644. However, others report that within hours of intra-articular administration, aseptic acute arthritis develops, which may be caused by pro-inflammatory HA degradation products. Bernardeau et al., Ann Rheum Dis 2001; 60:518-20. A French study considered that a single HA injection may not have much effect on the knee because it may be rapidly cleared from the synovial fluid compartment. Thus, the research regarding the use of HA appears inconsistent; however, while HA may eventually prove to be useful, intra-articular injection of exogenous HA still remains a significant concern. For completeness, the AAOS 2008 guideline publication on non-arthroplasty treatment did not recommended for or against the intra-articular administration of HA.
Administration of chondroitin sulfate is also considered a potential candidate for treatment. Chondroitin sulfate is a sulfated gycosaminoglycan (GAG) composed of alternating sugars of N-acetyl galactosamine and glucuronic acid. It is an important structural component of cartilage and provides much of its resistance to compression. Baeurle et al, Polymer 2009; 50:1805-13. The AAOS 2008 guideline publication did not recommend the use of chondroitin sulfate. The AHRQ report stated that “the best available evidence found that glucosamine hydrochloride, chondroitin sulfate, or their combination did not have any clinical benefit in patients with primary OA of the knee.”
As the name implies, alternative medicine provides alternatives to conventional medical treatment or management of OA. It has been said that “[w]hat most sets alternative medicine apart, in our view, is that it has not been scientifically tested and its advocates largely deny the need for such testing.” Kassirer, New England Journal of Medicine 1998 September; 339(12)839-41. Since many therapies lack scientific studies, typically the AAOS does not recommend for or against such treatments.
Among the alternative medicine approaches, one of particular interest is the use of “nutraceuticals.” Nutraceutical, a term combining the words “nutrition” and “pharmaceutical,” was originally defined by Dr. Stephen L. DeFelice to describe a nutritional product that claims to provide medicinal benefits in addition to their regular nutritional value. Nutraceuticals is a broad term, which can refer to foods, dietary supplements, medical foods and functional foods that may provide prevention and treatment of illness or disease. Importantly, nutraceutical foods are not subject to the same testing and regulations as pharmaceutical drugs. However, nutraceuticals have become increasingly mainstream and can be considered a dietary approach or nutritional approach since the extracts or foods are typically orally ingested.
Nutraceuticals for most part are extracts of botanicals. They are mixture of various materials, some known and other unknown. Thus, the knowledge of their metabolism is often unknown. They are described as belonging to various chemical groups, which in order of progression from general to specific are as follows, with each successive being a sub group. In fact, the absence of testing and scientific standards tend to confuse consumers and the scientific community as to what the mixtures actually are, their activity and biological effect.
Among the common nutraceuticals are antioxidants, in particular Vitamin C and E. The pharmacophore of vitamin C is ascorbate ion and is required for a range of essential metabolic reactions in animals. Ascorbate ion protects the body against oxidative stress and is cofactor in several vial enzymatic reactions. Vitamin E is a fat-soluble antioxidant that stops the production of reactive oxygen species formed when fat undergoes oxidation. NTH, Vitamin E Fact Sheet, 2009 May. Each are recommended for a wide variety of medical conditions even without scientific basis.
In recent years the poly phenols have been popularized, including anthocyanins and anthocyanidins. Attention has been drawn to their potential to benefit articular cartilage nutrition. Experiments with direct application of such products to articular cartilage and cells have shown they enhance the growth hormone production within the cartilage and have an antioxidant effect. One such report was that of Miller et al. Progrado, which is an extract enriched for long chain proanthocyanin oligomers, was reported to have a promising safety profile, significant chondroprotective and antioxidant actions, directly inhibit MMP activity and promote the production of cartilage repair factor, insulin-like growth factor-1 (IGF-1), in explants and cell culture which suggested it may offer therapeutic benefits in joint health, wound healing and inflammation. Miller et al., Journal of Inflammation, 2007; 4:16. However, Miller acknowledges that repair and cartilage growth was not measured. Thus, while promising in vitro, the results did not transfer to desired activity in vivo. Closer inspection of Miller's report reveals there is little characterization of the ingredients. That is, the extracts are not synthesized, pharmaceutically pure or well characterized ingredients, but instead includes a collection of unknowns suspected of including oligomers referred to as proanthocyanins. That is, it appears the compounds in Miller are considered to be oligomeric chains or long polymer chains; however, the chains themselves are not well defined. Consistent with unknown extracts or elixers, Progrado is provided as a nutraceutical and is thus exempt from characterization necessary to understand relevant structures or ingredients. This is consistent with its labeling as a dietary or nutritional supplement, which further confuses the matter. Accordingly, it is not in fact clear what the active ingredients may be in Progrado, if any. That is, while Miller provides an extract believed to be enriched in proanthocyanin oligomers, the ingredients themselves, including the “oligomers” remain to be characterized. Nonetheless, it is an object of Miller to provide extracts for oral ingestion to deliver dietary or nutritional supplemental ingredients to their intended target.
In fact, the assumption that the oral intake of food or extracts of food would reach the articular cartilage in the synovial joint has not been supported by any evidence. The marketing of nutraceuticals is not under FDA control and therefore may make claims accompanied by “disclaimers” of the benefits to articular cartilage. The evidence from the nutrition literature would indicate the likelihood of ingested food or extracts reaching the synovial joint is remote. That is, the lack of desired in vivo activity in the Miller et al. experiment appears consistent with the literature regarding the metabolism of flavonoids in the body. In 2007 it was found that inside the body, flavonoids themselves are of little or no direct antioxidant value. Lotito et al., Free Radic. Biol. Med. 41(12)1727-46. Body conditions proved to be unlike controlled test tube conditions, and the flavonoids were found to be poorly adsorbed (less than 5%), with most of what is absorbed being quickly metabolized and excreted. It has been theorized that increase in antioxidant capacity of blood seen after consumption of flavonoid-rich foods is not caused directly by the flavonoids themselves, but due to increased uric acid levels that result from expelling flavonoids from the body. Frei, EurekAlert! 2007 March, news release by Oregon State University. According to Frei, large doses of dietary supplements might do no additional good over a relatively modest intake since the body sees them as foreign compounds and modifies them for rapid excretion in the urine and bile. Based on Frei's findings, flavonoids appeared to have 3-5 times more antioxidant capacity than vitamins C or E but since flavonoids were poorly absorbed in the body (less than about 5%) vitamin C accumulated more in cells where it is 1,000 to 3,000 times more active as an antioxidant.
The lack of in vivo activity in the Miller et al. study is also consistent with the half-life of flavonoids. For instance, the anthocyanin cyanidin-3-glycoside has a half-life of about 90-120 minutes. This may be due in part to the surrounding acidic pH, which is substantially different than the approximate neutral pH of the bloodstream. As such, these compounds would not be predicted to cross biological barriers to affect the cartilage. Thus, considerations of flavonoids for potential treatments must account for their in vivo challenges from oral ingestion to end target tissue.
By way of contrast, a pharmaceutical is a well-defined substance. It is usually a single molecule, occasionally a compound, and most often not in oligomeric chains. They are closely regulated by the FDA. The foundation for their efficacy and safety are a necessity. Their use in clinical practice require more rigorous testing prior to market approval as with various phases of clinical trials. Pharmaceuticals are administered by gastrointestinal route and/or bodily injection. After FDA approval, the process of oversight continues. This is in stark contrast to the less demanding foundation or process for marketing a nutraceutical.
Therefore, if in fact these polyphenols are a benefit to the articular cartilage, there is a need to consider the efficacy and safety of the direct application by injection. There is a need for such a novel method and specific substances that are not a food extract of a mixture of molecules known and often unknown, but molecules or compounds of pharmacological composition and purity to achieve a therapeutic benefit to articular cartilage.
Glucose is a building block of many tissues including cartilage, where the main product produced by the cartilage cell are mucopolysaccharides, which form a network of matrices that hold a high percentage of water. Thus, some believe glucose itself may be a potential candidate for the treatment of arthritic conditions. For instance, dextrose injections in the knee and base of the thumb showed repair and clinical improvement from osteoarthritits. Reeves et al, Alt Ther Hlth Med 2000; 6(2):37-46. Afterwards, a three year consecutive patient study of 10%-25% dextrose injection in patients with ACL laxity, 87% of whom had osteoarthritis, had improved tightening of the ACL and decreasing symptoms of osteoarthritis. Reeves et al., Alt Ther Hlt Med 2003 May-June; 9(3)58-62. Tissue regeneration in articular cartilage in rabbit has also been shown with 10% dextrose by injection. Kim et al., J Korean Acad Rehabil Med 2006 April; 30(2):173-178. Though studied alone, it has also been proposed to use a combined therapy with glucose. However, when coupled with amino acids, injection of 10% dextrose showed no measurable improvement compared to 10% dextrose alone. Park et al., Arthritis Research and Therapy, 2007; 9(1):R8.
Glucose is an attractive candidate since it is ever present in all body tissues as well as synovial joints, including the synovium, the synovial fluid and cartilage; however, glucose levels in the synovial fluid are less than those in the blood. It may be that increasing glucose concentration stimulates human ostearthritic synovium to make hyaluronic acid (HA). The addition of 5 mM glucosamine increased HA production approximately 2-fold in osteoarthritic synovium explants but 0.5 mM glucosamine did not. Uitterlinden et al., BMC Muscoskeletal Disorders 2008:9:120. Thus, it appears physiologic levels of glucose may be insufficient for stimulating HA production.
Further, although glucose has been shown to provide an anabolic effect on cartilage it does not have a chondroprotective effect. That is, while cartilage can be formed, its formation merely mitigates its loss.
Insulin-like growth factor-1 (IGF-1) is also considered to be a potentially viable treatment for cartilage conditions. It has been known for years that IGF-1 is chondroreparative. IGF-1 is believed to play a key role in cartilage homeostasis, balancing proteoglycan synthesis and breakdown. Schmidt et al., Osteoarthritis Cartilage, 2006 May; 14(5):403-12. The action of IGF-1 on chondrocytes is mediated through the IGF-1 receptor. Taylor et al., FEBS Lett. 1988; 236:33-8. Composites of chondrocytes and polymerized fibrin were supplemented with IGF-1 during arthroscopic repair of full-thickness defects in horses and were shown to improve the repair capabilities of chondrocyte-fibrin grafts. Fortier et al., J Bone and Joint Surg 2002 March; 84-B(2)276-288. Although IGF-1 is naturally present in the synovium (see Keyszer et al., J. Rheumatol. 1995 February; 22(2)271-81), the total IGF-1 in normal human synovial fluid is an order of magnitude lower than that in the serum. Schneiderman et al., Arch Biochem Biophys 1995 December; 324(1):173-88. However, IGF-has been shown to be elevated in the synovial fluid of patients with osteoarthritis, in contrast to decreased levels of IGF-II and neutral levels of IGFBP-3. Matsumoto et al., Journal of Clinical Endocrinology and Metabolism 1996; 81:150-5. Increased IGF-1 production by human osteoarthritic chondrocytes is not dependent on growth hormone action. Dore et al., Arthritis and Rheutism, 1995; 38(3):413-419. Thus, effective stimulation of IGF-1 may require additional experimentation.
While IGF-1 is believed to increase cartilage production, exogenous administration of IGF-1 as well as human growth hormone (HGH) possess risks to patient health. Although IGF-1 is believed to enhance proliferation of cells and thus may also enhance proliferation of chondrocytes, it is believed to do so by inhibiting apoptosis, which includes apoptosis of cancer cells. Smith et al., British Medical Journal, 2000; 321:847-48. In fact, many studies have implicated IGF-1 in carcinogenesis. See Grmberg et al., J Cell Physiol 200 April; 183(1):1-9.
Insulin is known to bind to the IGF-1 receptor and to illicit significant responses in cartilage. Kellner et al., J Drug Target, 201; 9(6):439-8. Thus, insulin may also be a promising approach for cartilage healing. Administration of a slow release formulation of insulin was provide to cartilaginous explants, which resulted in the stimulation of proteoglycan (PG) synthesis, inhibition of PG release and nitric oxide production and overcame detrimental effects of interleukin-1 (IL-1). Cai et al., Osteoarthritis Cartilage, 2002 September; 10(9):692-706. At one time it was believed that only the islet cells of the pancreas would produce insulin; however, many other cells are known to produce insulin under certain conditions. Adult stem cells from the intestine have been converted into insulin-producing beta cells in the pancreas of diabetic mice. Suzuki, PNAS 10.1073/pnas.0936260100. Stem cells extracted from the spleen can change into insulin-producing pancreatic islet cells. Fasutman et al, Science 2003 November; 302; 1123-1127. Bone marrow stem cells transplanted into the pancreas can morph into insulin-producing beta cells. Mehbood et al., Journal of Clin. Investig. 2003 March; 111(6). Adult hepatic progenitor cells can be induced into insulin-producing cells. Nagata et al., Biochem. Byophys. Res. Commun. 318:625-630. Thus, the production of insulin may be approached using a variety of cell types found throughout the body given the proper environment.
Joint replacement is the only established treatment for end-stage OA. In the case of the knee, the cost for such an operation is high—an estimated $35,000 for those without health insurance and the operation also typically entails a 3-7 day hospital stay. During the surgery the doctor assesses the condition of the joint surfaces, removes damaged bone and cartilage, and implants new joint surfaces made of plastic and metal. These new joint surfaces are not permanent, and will likely need to be replaced after 10 to 15 years. Alternative surgical procedures can include debridement procedures, which include arthroscopic procedures for mechanical problems and loose bodies; and osteotomy, which is a procedure to alter the forces across the joint.
While conventional thought is that articular cartilage has no potential for repair, studies are currently underway to explore the use of the synovium, which is the soft tissue that lines the non-cartilaginous surfaces. The synovium is believed to have regenerative capabilities. The surgical removal of the synovium of laboratory rabbits resulted in regeneration of the synovium to prior status in 6 weeks. Key et al, J Bone Joint Surg Am 1925; 7:793-813. The same is true in humans. Ostergaard et al, Ann Rheum Dis 2001; 60:233-236.
One such proposed treatment involves the use of synovium explants. U.S. Pat. No. 7,575,743 by Hunziker proposes using an excised sheet of synovial membrane as an explant for the treatment of a shallow cartilage defect. More specifically, synovial cells are harvested from the synovial membrane, cultured, then used to fill a cartilage defect together with a transforming factor. The theory behind this procedure is that synovium adjacent to the articular cartilage reflection will migrate and heal cartilage lesions in the immediate proximity of the reflection, but not those remote to the intact synovium. Hunziker et al., J Bone Surg [Am] 1996; 78-A; 721-733. Thus, use of synovium tissue treated in this manner may prove useful.
In a more elegant procedure, US Patent Publication 2006/0051327 by Johnson proposes a treatment including the removal of synovial villi from the synovial capsule and its use as an explant. The synovial villi are the finger-like projections that exist in some instances of joint injury and/or disease. These villi are known to house red blood cells, white blood cells as well as plasma with circulating electrolytes, growth hormones, and circulating insulin. In addition the synovial villi have increased number of synovial cells in depth and extended surface area. There are also mesenchymal stem cells (MSC). As such, stem cells and other beneficial components found within the villi, if transferred, would assist in repair while portions of the synovium, which remain, are permitted to rebuild the synovial membrane at the site of harvest in furtherance of Key et al. In addition, there are primary repair cells, fibroblasts and angioblasts, which may also contribute to repair of cartilage.
Although synovium explants have been demonstrated to heal damaged cartilage, the methods still require surgical processes, which can be expensive and provide additional health risks. Accordingly, there remains a need to develop compositions that stimulate or enhance the production of articular cartilage and that reduce or eliminate the need for surgical intervention or that increase the rate of healing from surgery.
Thus, while numerous approaches for the treatment of OA conditions have been proposed, there remains a need to provide improved therapies that address the biological activity of the molecule as well as the potential innate barriers the body possesses against delivery to the affected joint.